International Journal of Women's Dermatology 3 (2017) 11–20

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International Journal of Women's Dermatology

Review

A review of laser and light therapy in melasma

M.K. Trivedi, BS, BA a,b,⁎, F.C. Yang, MD c, B.K. Cho, MD, PhD d
a
University of Michigan Medical School, Ann Arbor, Michigan
b
Department of Dermatology, University of California San Francisco, San Francisco, California
c
Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
d
Department of Dermatology, Palo Alto Medical Foundation, Sunnyvale, California

a r t i c l e i n f o a b s t r a c t

Article history: Melasma is a dysregulation of the homeostatic mechanisms that control skin pigmentation and excess pig-
Received 29 November 2016 ment is produced. Traditional treatment approaches with topical medications and chemical peels are com-
Received in revised form 18 January 2017 monly used but due to the refractory and recurrent nature of melasma, patients often seek alternative
Accepted 19 January 2017
treatment strategies such as laser and light therapy. Several types of laser and light therapy have been stud-
ied in the treatment of melasma. Intense pulsed light, low fluence Q-switched lasers, and non-ablative frac-
tionated lasers are the most common lasers and light treatments that are currently performed. They all
appear effective but there is a high level of recurrence with time and some techniques are associated
with an increased risk for postinflammatory hyper- or hypopigmentation. The number and frequency of
treatments varies by device type but overall, Q-switched lasers require the greatest number of treatment
applications to see a benefit. Vascular-specific lasers do not appear to be effective for the treatment of
melasma. Ablative fractionated lasers should be used with caution because they have a very high risk for
postinflammatory hypo- and hyperpigmentation. The use of nonablative fractionated laser treatments
compared with other laser and light options may result in slightly longer remission intervals. Picosecond
lasers, fractional radiofrequency, and laser-assisted drug delivery are promising future approaches to
treat melasma. The goal of this review is to summarize the efficacy and safety of the most commonly
used laser and light therapies to treat melasma, briefly present future laser-based treatment options for pa-
tients with melasma, and provide recommendations for treatment on the basis of the reviewed
information.
© 2017 Women's Dermatologic Society. Published by Elsevier Inc. This is an open access article under the CC
BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction progesterone pathways, genetic predisposition, and/or inflammation

Melasma is a common and well-described dermatological condi-
tion that primarily affects female patients. It involves hyperpigmen-
tation that is chronic, relapsing, and characterized by symmetric,
brownish-grey macules and patches on the face and sometimes the
neck, chest, and forearm. Melasma has also been referred to as
chloasma or “the mask of pregnancy” because the condition is often
associated with women who are pregnancy (Wong et al., 1984).
The condition is otherwise asymptomatic and there is no clear associ-
ation with a systemic illness but melasma can be psychosocially det-
rimental to many patients.
There is currently no definite etiology but multiple factors includ-
ing ultraviolet radiation, hormonal alterations within the estrogen or
⁎ Corresponding Author.
E-mail address: mtrivedi41@gmail.com (M.K. Trivedi).
have all been implicated and recently reviewed (Lee, 2015). Melasma
may also have a vascular component as some studies have found
melasma-affected skin to have increased vascularity (Kwon et al.,
2016). The common outcome from these diverse triggers is an in-
creased synthesis of melanosomes in melanocytes and an increased
transfer of melanosomes to keratinocytes. Women with darker skin
types (i.e., Fitzpatrick skin type IV-VI) are most commonly affected
(Grimes, 1995).
Melasma is classified by both location and depth of involvement.
The three most common types of melasma are centrofacial, malar,
and mandibular, which describe the patterns of facial involvement.
Melasma can be further characterized by the depth of involvement,
which is often assessed by Wood’s lamp illumination and divided
into four categories: epidermal, dermal, mixed, and indeterminate
(Grimes et al., 2005). Histologically, increased melanin in epidermal
keratinocytes, dermal macrophages, or both are present (Kang et al.,

http://dx.doi.org/10.1016/j.ijwd.2017.01.004
2352-6475/© 2017 Women's Dermatologic Society. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
12 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
2002). Wood’s lamp can help distinguish between these entities be-
cause enhancement under the lamp suggests epidermal type and
nonenhancement suggests dermal type. However, this assessment
does not always correlate with histological findings and melasma
that is labeled epidermal is often mixed with areas of dermal involve-
ment (Grimes et al., 2005). Thus, Wood’s lamp does not fully differen-
tiate between mixtures of epidermal and dermal melasma but is the
best method to demonstrate dermal melasma, which is less likely to
respond to topical therapy.
An alternative classification with noninvasive reflectance confocal
microscopy (RCM) has been suggested because it uses the ratio of
epidermal-to-dermal melanin that involves the whole lesional skin
(Ardigo et al., 2010). An advantage of RCM analysis is that it can non-
invasively and accurately categorize the subtype of melasma as well
as quantitate the response to therapy. However, RCM quantitation
of melasma severity is still in its infancy.
Treatment strategy
The treatment regimen of patients with melasma typically starts
with the management or elimination of risk factors, strict ultraviolet
sun protection, and topical lightening formulations. Topical treat-
ments may temporarily improve the skin but the condition often
returns. The principles of therapy include the inhibition of pathways
that synthesize melanin, decrease of melanosome transfer from me-
lanocytes to keratinocytes, and acceleration of pathways to remove
melanin.
Topical agents
The current first-line treatment for melasma is topical agents. The
major group of topical agents to be considered are those that disrupt
the enzymatic processes of pigment production within melanocytes.
Tyrosinase is the rate-limiting enzyme in the melanin production
process that converts L-tyrosine to L-3,4-dihydroxyphenylalanine
(L-DOPA) and is the major target for many of these agents. Melanin
is synthesized through a series of steps and converts the base precur-
sor tyrosine to DOPA and then to dopaquinone, which is converted to
dopachrome and eventually to eumelanin (Hearing, 2011). These
types of treatments include hydroquinone (often used in combina-
tion with tretinoin and a topical steroid), arbutin, azelaic acid, and
kojic acid. Ascorbic acid is also another inhibitor of melanogensis
through its antioxidant effects and interaction with copper ions in
the tyrosinase active site (Sarkar et al., 2013).
Other targets for intervention in the melanin synthetic pathway
include the interaction between keratinocytes and melanocyte.
There are several botanical agents such niacinamide and soy that
act through protease-activated receptor-2 (PAR-2) and inhibit the
transfer of melanosomes to the surrounding keratinocytes (Sarkar
et al., 2013). Serine protease inhibitors, lecthins, and neoglyco-
proteins also affect this pathway (Briganti et al., 2003).
Improving skin turnover is another therapeutic route for the
treatment of melasma. Agents that accelerate skin turnover include
glycolic acid, linoleic acid, lactic acid, liquiritin, retinoic acid, and
Helix aspersa müller. Certain fatty acids such as linoleic or α-
linoleic acid may induce the degradation of tyrosinase (Briganti
et al., 2003).
An overview of topical melasma treatments was recently pub-
lished by Ball Arefiev and Hantash (2012) and Sehgal et al. (2011).
Topical treatments may be unsatisfactory due to a lack of re-
sponse, slow rates of improvement, or adverse events such as
pseudo-ochronosis with hydroquinone or skin irritation, erythe-
ma, and postinflammatory hyperpigmentation (PIH; Ball Arefiev
and Hantash, 2012; Sehgal et al., 2011).
Chemical peels
The addition of chemical peels to a topical treatment regimen is
second-line treatment as peels help accelerate the elimination of
pathways for melanin. Superficial peels such as glycolic acid, Jessner,
and retinoic acid are typically selected because they tend to have the
least risk of complications and exacerbation of pigmentation if there
is too much inflammation or irritation. Peels have been shown to be
effective, especially when used in a series of treatments (Sheth and
Pandya, 2011). Chemical peels may cause melasma rebound or PIH
due to irritation or inflammation.
Laser- and light-based treatments
Laser and light therapy represent an alternative third-line ap-
proach to treat melasma and may be particularly beneficial for pa-
tients with melasma that is refractory to topical therapy or
chemical peel regimens, or when a patient wishes for an accelerated
pace of improvement. Analogous to chemical peels, these modalities
accelerate the removal of pathways for melanin but do not target the
melanin production itself. One key point of patient counseling prior
to laser- and light-based treatment is that these therapies have the
potential to speed up the removal of melasma-related hyperpigmen-
tation but they are not cures for melasma. Furthermore, they present
a risk for PIH or a rebound melasma flare. Optimal treatment man-
agement of difficult cases should include a combination therapy
whereby a topical regimen inhibits melanin production and/or mela-
nosome transfer and a procedure accelerates melanin removal.
The lesions of melasma are not the only hyperpigmented lesions
that are successfully treated with laser and light therapy. Hori’s
nevus, which often appears as macular blue-gray lesions in a bilateral
facial distribution similar to melasma, has been successfully treated
with Q-switched lasers in a handful of studies within the last 2 de-
cades. This suggests that laser and light therapy holds promise as an
effective treatment for a variety of hyperpigmentation conditions
(Polder et al., 2011).
Overview of laser- and light-based treatment options
The theory of laser therapy to treat cutaneous disorders was first
explored by Anderson and Parrish in 1983. They noted that
pigmented structures within tissue demonstrated specific thermal
and absorptive properties that allowed them to be targets for selec-
tive destruction with specific wavelengths of radiation while sparing
the surrounding tissue. Therefore, various targets that range from un-
wanted hair to tattoo ink could be specifically targeted for removal
with minimal effect on the surrounding normal skin. Since that
time, light and laser therapies have been used for multiple dermato-
logic and cosmetic conditions including vascular birth marks, telangi-
ectasias, hypertrichosis, tattoos and pigmented lesions, solar
lentigines, lentiginous nevi, café -au-lait macules, and melasma
(Patil and Dhami, 2008).
Laser therapy for the treatment of melasma has become an alter-
native to the more common treatments with topical creams and
chemical peels, especially for patients with refractory cases. A multi-
tude of different lasers therapies have been studied in numerous clin-
ical trials to date and a vast range of efficacies and adverse events
have been demonstrated. Frequently, the outcomes of these studies
are reported through physician-graded assessments or changes in
the melasma area severity index (MASI). The five broad categories
of laser and light therapy include intense pulsed light (IPL), Q-
switched lasers, picosecond lasers, nonablative fractionated
resurfacing lasers, and ablative fractionated resurfacing lasers. The
objective of this review is to comment on both the efficacy and safety
of the most commonly used laser and light therapies for the
 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
treatment of melasma as published in the current literature and pres-
ent new device-based treatment options that are currently in devel-
opment for patients with melasma.
Intense pulsed light
IPL therapy uses a flash lamp light source that emits noncoherent
light with wavelengths between 515 nm and 1200 nm. Filter sets
allow for the targeting of selective chromophores (melanin vs. hemo-
globin) and has been used to treat various pigmentary disorders. Its
potential advantage over laser therapy is that it uses a spectrum of
wavelengths that allow for the penetration of various levels of the
skin and target both epidermal and dermal melasma simultaneously.
The pulse duration of IPL is in the millisecond range and provides
greater thermal diffusion and a reduced chance of thermal-related
postinflammatory pigmentation. The size of the IPL head is larger
than most laser spot sizes, which allows for the rapid treatment of
large areas.
Wang et al. (2004) compared the application of a 4%-hydroqui-
none cream versus 4% hydroquinone plus IPL in a prospective ran-
domized control trial in which 17 patients were treated with four
sessions of IPL over a 16-week period. A spectrophotometer was
used to measure a relative melanin index, defined as the difference
between the melanin index of lesional skin and the melanin index
of normal skin. After treatment completion, the group of patients
that was treated with IPL plus hydroquinone demonstrated a reduc-
tion of 39.8% in relative melanin index compared with 11.6% for the
patients in the control, hydroquinone-only treatment group
(p b .05). Although the study demonstrated the effectiveness of IPL
as a potential treatment, two patients developed PIH and 24.2% of
the participants who improved with IPL developed recurrent pig-
mentation within 24 weeks post-treatment (Wang et al., 2004).
Side effects of the therapy with IPL included crusting that lasted 1
to 2 weeks.
Goldman et al. showed that IPL could be particularly helpful to
treat moderate-to-severe melasma if combined with more aggressive
topical maintenance treatment to minimize pathways for pigment
recurrence. The researchers completed a 10-week study of 56 pa-
tients who were randomized to receive either IPL with a triple com-
bination cream (TCC) or IPL with a placebo cream (PC). The TCC
contained 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone
acetonide. At week 10, 57% of patients in the IPL with TCC group
were clear or almost clear in contrast to 23% of patients in the IPL
with PC group (Goldman et al., 2011). A similar finding was reported
by Figueiredo and Trancoso (2012) who compared outcomes of pa-
tients treated with IPL and TCC versus TCC therapy alone. The MASI
scores of patients in the IPL/TCC group showed a 49.4% reduction
from baseline at 6 months and maintained a 44.9% reduction from
baseline at 12 months (Figueiredo and Trancoso, 2012).
The effectiveness of IPL therapy on epidermal versus other mixed
melasma was assessed by Li et al. (2008) who found that 77.5% of pa-
tients obtained N51% of improvement after four IPL therapy sessions
by dermatologist assessment. Mean MASI scores decreased from 15.2
to 4.5. Patients with the epidermal type of melasma responded better
to treatment compared with those with the mixed type (Li et al.,
2008).
Overall, IPL therapy appears to give modest improvement in pa-
tients with melasma that is refractory to topical therapy alone but
have a modest recurrence rate unless an aggressive topical therapy
is maintained at least 6 to 12 months post-treatment. IPL therapy is
best suited to treat patients with Fitzpatrick skin types 1 to 3 because
use with patients who have a darker skin type carries an elevated risk
to target normal endogenous skin pigment. Patients with epidermal
melasma may respond more favorably to IPL therapy compared
with those with mixed or dermal melasma.
13
Q-switched lasers
Q-switched lasers produce high intensity laser beams with very
short pulse durations. The speed of a Q-switched laser pulse is ap-
proximately one million times that of an IPL pulse. Q-switched lasers
that target melanin are available in multiple wavelengths including
ruby (694 nm), alexandrite (755 nm), and neodymium-doped yttri-
um aluminum garnet (Nd:YAG; 532 nm or 1064 nm). Because
these lasers are standard therapies for the removal of birthmarks,
solar lentigines, and tattoos, they were expected to be effective for
the treatment of patients with melasma as well. However, the results
from studies on the use of Q-switch lasers were disappointing and
treatments were complicated by significant rebound hyperpigmenta-
tion. In the publication of the results from one trial that studied the
effects of the Q-switched ruby laser to treat patients with melasma
and PIH that is refractory to other treatments, the authors noted
that there was no improvement and in some cases a deterioration
with the laser treatments regardless of the fluence. Several months
after the last treatment, epidermal pigmentation was back to baseline
levels and dermal melanophages were increased (Taylor and Anderson,
1994). In a split-face trial that studied the effectiveness of the Q-
switched ruby laser versus an erbium:yttrium-aluminum-garnet
(Erb:YAG) laser to treat pigmented lesions, the investigators
found that the three study patients who were treated for melasma
were the only participants who did not have an improvement in
their condition. In fact, the patients with melasma developed PIH
and deteriorated as a result of the therapy (Tse et al., 1994).
Angsuwarangsee and Polnikorn (2003) conducted a split-face
study where half of the patients’ face was treated with a Q-
switched alexandrite laser and the other half with combined car-
bon dioxide (CO2) and Q-switched alexandrite laser therapy. The
side that was treated with the Q-switched alexandrite laser did
not show a significant benefit and two of six patients who were
enrolled in the study developed severe PIH (Angsuwarangsee
and Polnikorn, 2003).
A new variant of Q-switched laser use called low fluence or
subthermolytic Q-switched treatment is gaining increasing populari-
ty. The lasers are the same but the fluences are lower than those that
are traditionally used to treat pigmented lesions. The low-fluence
treatments largely utilize the 1064 nm wavelength, which penetrates
deeper into the dermis and leaves the epidermis relatively spared.
The treatment of patients with melasma with subthermolytic low
fluences is based on the theory that the pigment disruption takes
place through a photoacoustic mechanism that breaks apart the pig-
ment only and spares the keratinocytes and melanocytes from de-
struction. However, there is often some degree of damage that
accompanies subthermolytic Q-switched treatment but this damage
is reported to be less than that from traditional photothermolytic
treatment.
A 2010 split-face randomized study by Wattanakrai et al. (2010)
treated 22 patients with Fitzpatrick skin types III to V with dermal
or mixed type melasma and compared treatment with low-fluence
Q-switched Nd:YAG laser and topical 2% hydroquinone versus 2%
hydroquinone alone. Each patient was treated with 3.0 J/cm 2 to
3.8 J/cm2, 6 mm spot size at 10 Hz for five sessions at one week inter-
vals. The researchers found that the laser-treated side of the face
achieved an average of 92.5 % improvement in relative lightness
index versus 19.7 % on the hydroquinone-treated side. There was also
a 75.9 % improvement in the modified MASI (mMASI) score on the
laser-treated side versus 24 % on the hydroquinone-treated side. How-
ever, three of 22 patients (all with Fitzpatrick skin type V) developed
mottled hypopigmentation after five laser treatments and eight pa-
tients developed confetti type hypopigmentation. Three months after
treatment, four patients had developed rebound hyperpigmentation
and there was a 100% recurrence rate although the degree of lightening
14 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
on the laser-treated side was still greater than or equal to the degree of
lightening on the control side (Wattanakrai et al., 2010).
The high melasma recurrence rate despite use of Q-switch
treatment at low fluences was also found in a study by Xi and col-
leagues in which 50 patients were treated with 9 weekly treat-
ments with a 1064 nm Qs Nd:YAG laser. The study results
demonstrated a 61.3% mean decrease in MASI score after the
ninth treatment but there was a 64% recurrence rate 3 months
posttreatment. This study was also interesting because several
patients completed RCM imaging throughout the study. These
imaging studies showed that the Q-switched laser was effective
at removing melanin particles in the basal layer but by the 3-
month follow-up examination, melanin levels had largely
returned to the baseline level (Xi et al., 2011).
A prospective investigator-blinded study by Hofbauer Parra et al.
(2016) in which 20 Brazilian patients received 10 laser treatments
demonstrated decreased mMASI scores from 7.85 to 4.33 (p b.001)
after the final treatment. Recurrence rates were similar to those in
previous studies with an 81% recurrence rate at 3-months posttreat-
ment. However, no severe side effects such as hypo- or hyperpigmen-
tation were reported, leading the authors to conclude that low-
fluence Q-switched Nd:YAG laser therapy is safe to treat patients
with melasma. However, the high recurrence rates suggest poor
long-term results when the laser is used as a monotherapy
(Hofbauer Parra et al., 2016).
Similar to IPL treatments, the use of topical hydroquinone prepa-
rations can help reduce melasma recurrence and one study suggests
that pretreatment hydroquinone is more effective than posttreat-
ment hydroquinone (Jeong et al., 2010). Of note, the U.S. Food and
Drug Administration (FDA) approved Lutronic’s dual-pulsed Q-
switched Nd:YAG laser, Spectra, in 2012 for the treatment of patients
with melasma. It is the first and only approved Q-switched laser ther-
apy for the treatment of patients with melasma.
In summary, Q-switched laser therapy at the fluences that is used
to treat benign pigmented lesions has not been effective. Low-fluence
Q-switched laser therapy and in particular Nd:YAG has shown some
initial promise but requires multiple treatments over a relatively
short treatment interval (weekly) and has extremely high 3-month
recurrence rates (64%-81%). The number of required treatments is
generally more than those for other light- and laser-based treatment
modalities. Several recent studies suggest that fractionating the laser
energy (Yue et al., 2016) or combining low-fluence Q-switched lasers
with long-pulsed Nd:YAG (laser toning [Kang et al., 2011] or IPL
[Vachiramon et al., 2015; Yun et al., 2014]) may reduce the recur-
rence rate. However, until the recurrence rate is reduced significantly
in a reproducible way and the relatively high rates of posttreatment
dyspigmentation are resolved, Q-switched laser therapy for patients
with melasma is likely reserved for very recalcitrant cases that have
failed with other laser modalities first.
Nonablative fractionated resurfacing lasers
Fractional resurfacing, which was introduced in 2004, creates se-
lective columns of microthermal damage in which treated areas are
intermixed with untreated ones. Thus, recovery is more rapid and
theoretically the resulting inflammation is lower, which lessens the
risk for scarring or dyspigmentation (Manstein et al., 2004). Fraction-
al resurfacing can be broadly categorized into nonablative fractional
laser (NAFL) and ablative fractional laser (AFL).
NAFL devices target water-containing tissues but create columns
of coagulative damage within the dermis that are below the ablative
threshold. The stratum corneum is intact throughout the treatment
and a visible wound does not occur. The most common affect imme-
diately posttreatment is erythema and swelling. Four NAFL wave-
lengths are used including 1440 nm, 1540 nm, 1550 nm, and 1927
nm. NAFL at 1440 nm, 1540 nm, and 1550 nm utilizes midinfrared
wavelengths that bypass the epidermis and penetrate from the
dermal-epidermal junction to the midreticular dermis (maximum
depth approximately 1500 microns) to induce neocollagenesis and
remodeling. The transepidermal elimination of these microthermal
treatment zones in the weeks posttreatment is hypothesized to facil-
itate the removal of dermal melanophages and be the main mecha-
nism for melasma improvement (Hantash et al., 2006). NAFL at the
1550 nm wavelength has been approved by the FDA since 2005 for
the treatment of patients with melasma. There is little published
data on the 1440 nm wavelength with regard to melasma treatment
although Kouba et al. (2008) suggested that it was beneficial to treat
another dermal melanocytic lesion, Nevus of Ota, and may have util-
ity toward dermal melasma (Kouba et al., 2008). Erythema, swelling,
and pain are common with NAFL at 1440 nm, 1540 nm, and 1550 nm
but these are short-term side effects that typically last for 3 to 10 days
and overall, this treatment is considered a low downtime, fast recov-
ery procedure. PIH is a reported side effect in most of the clinical tri-
als. The development of PIH seems to be correlated with the density
of the microthermal zones and possibly a byproduct of the heat that
is generated during treatment.
The initial studies with the laser of 1550 nm reported that six of 10
female patients with recalcitrant melasma had 75% to 100% clearance
at the 3-month interval after four to six treatments on the basis of
physician-graded assessments (Rokhsar and Fitzpatrick, 2005). Lee
et al. (2009) treated 25 patients with melasma with 1550 nm NAFL
monthly for four treatment sessions. Sixty percent of patients were
graded by investigators to have improved after completion of the
study but the number dropped to 52% at the 6-month posttreatment
assessment (Lee et al., 2009).
A direct comparison between NAFL with 1550 nm and triple ther-
apy topical cream to treat melasma was completed in a randomized,
controlled, observer-blinded study by Kroon et al. (2011). Twenty fe-
male patients with Fitzpatrick skin types II to IV either applied a mix-
ture of 5% hydroquinone, 0.05% tretinoin, and 0.1% triamcinolone
acetonide cream once daily for 8 weeks or received laser treatment
once every 2 weeks for a total of 4 treatments. Improvement as mea-
sured by the physician global assessment was equal between both
groups but treatment satisfaction and recommendation was higher
in the laser group. Recurrence was present in 50% of treated patients
in both groups at 6 months. No complications from PIH were report-
ed. The study investigators concluded that therapy with 1550 nm
NAFL was safe and comparable in efficacy and recurrence rate with
triple topical therapy. It may be a useful alternative treatment option
for patients with melasma when topical bleaching is ineffective or not
tolerated (Kroon et al., 2011).
Wind et al. (2010) performed a similar randomized study but
used a split-face approach where one side of the face was treated
with 1550 nm NAFL for four to five sessions and the opposite side
of the face received a triple therapy topical melasma cream (i.e., the
same cream used by Kroon et al., 2011). The mean physician global
assessment and patient satisfaction scores were significantly lower
for the side that was treated with the laser and 31% of patients
were reported with PIH. The authors concluded that the relatively
higher fluence that was used (15 mJ) versus the fluence used in the
Kroon study (10 mJ) could be a contributing factor (Wind et al.,
2010).
The efficacy of NAFL in combination with triple therapy topical
cream to treat melasma was assessed by Tourlaki et al. (2014) who
used a 1540-nm device to treat 76 patients with recalcitrant
melasma. Changes were assessed with MASI scores. At 1 month,
67.1% of patients had N75% clearing and 21% had 51% to 75% clearing.
At 6 months, only 21.1% of patients maintained a marked improve-
ment despite the application of the triple therapy topical cream
(Tourlaki et al., 2014).
 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
The 1927-nm NAFL laser was first introduced in 2009 and has
been used to provide superficial resurfacing primarily for hyperpig-
mentation. The thulium fiber 1927-nm laser has an approximate
10-times greater absorption coefficient for water compared with
the 1440-, 1540-, and 1550-nm lasers. Because of this, the 1927-nm
NAFL laser only penetrates to a maximal depth of approximately
200 microns, which corresponds to the general location of epidermal
melasma where melanosome and melanophages localize to the
dermo-epidermal junction (DEJ) and superficial dermis. Polder and
Bruce (2012) completed the pilot studies on 1927-nm NAFL therapy
and melasma. Fourteen patients with melasma were treated at 1-
month intervals and completed three to four treatments with
fluences of 10 mJ to 20 mJ and total densities of 252 MTZ/cm 2 to
784 MTZ/cm2. Participants had erythema, edema, and microcrust for-
mation that lasted approximately 3 to 7 days. No scarring or
postinflammatory hyper- or hypopigmentation was observed. Pa-
tient MASI scores improved 51%, 33%, and 34% at 1, 3, and 6 months
after completion of the treatment series, respectively (Polder and
Bruce, 2012), which suggests that the 1927-NAFL laser may offer
safe and effective treatment for patients with melasma.
Lee et al. (2013) completed a split-face single-blinded study of 25
Asian female patients with hyperpigmentation of whom eight pa-
tients had melasma. Fluence was set at 10 mJ, density at treatment
level 3, and patients received three treatments at 3-week intervals.
MASI scores on the treated side of the face improved 33% at 2 months
versus 5% on the control side. At 6 months posttreatment, the treated
side of the face maintained a 28% improved MASI score compared
with 12% on the control side. Histologic studies of the treated skin
showed reduced melanin levels but melanocyte density by Melan-A
immunostaining was unchanged. The treatment-associated discom-
fort was less than compared with 1550-nm NAFL treatment (Lee
et al., 2013).
The long-term efficacy of 1927-nm NAFL therapy was assessed by
Niwa Massaki et al. (2013) who completed a 12-month retrospective
review of 20 women with melasma who had completed a single
1927-nm NAFL treatment. Treatment settings ranged from 10 mJ/
cm 2 to 20 mJ/cm 2 with 60% to 70% surface area coverage, and total
energies from 1.72 kJ to 4.42 kJ. After treatment, patients maintained
treatment with 4% hydroquinone cream starting 1 month post-laser
treatment. Sixty percent of patients had more than 50% clearance of
their melasma 1 month after the single laser treatment session.
MASI scores continued to be improved 53.8% over baseline at 6
months to 12 months post-laser treatment. However, 33.3 % of pa-
tients reported at least a partial recurrence and 13% reported full re-
currence of melasma on average by 10.2 months after laser
treatment. Treatment of two patients was complicated by PIH,
which resolved within 3 months of treatment. The investigators con-
cluded that 1927-nm NAFL therapy offered good clearance of
melasma in a single treatment in contrast to NAFL therapy with
1440-, 1540-, and 1550-nm lasers, which required four to six treat-
ments to reach similar endpoints (Niwa Massaki et al., 2013).
NAFL treatment in general seems to offer a more durable response
in comparison with IPL and Q-switched laser treatments especially
when patients maintained treatment with a topical anti-Tyrosinase
cream before and after treatment. Although there is recurrence
with all NAFL treatments, the data suggests that recurrence occurs
between the 3 month to 6 month range whereas IPL and Q-
switched laser recurrence tends to occur before 3 months The num-
ber of treatments that are required for a benefit with NAFL seems
comparable with those that are reported for IPL (approximately
four) and approximately 50% fewer treatments compared with Q-
switched laser therapy, which is often done weekly for eight to ten
treatments.
NAFL with the 1927-nm device may offer more effective single
treatment response compared with all other devices although the
15
type of melasma (epidermal or dermal) that 1927-nm NAFL is best
suited for has yet to be determined. The benefit of NAFL is its ability
to treat a wider range of skin types including Fitzpatrick skin types
III to VI compared with IPL and Q-switched lasers, which should
only be used on skin types I to III. Lastly, because of the fractionated
mechanism, NAFL may also be better at blending melasma with the
surrounding unaffected skin.
Ablative fractionated resurfacing lasers
Ablative fractionated resurfacing lasers (AFL) such as CO2 lasers
and erbium:YAG lasers have been reported for the treatment of pa-
tients with melasma (Morais et al., 2013). The CO2 laser emits a
10,600-nm wavelength, which is strongly absorbed by water in the
skin cells. The penetration depth is dependent on the water content
and independent of either melanin or hemoglobin. A fractionated ap-
proach decreases the amount of epidermal injury and therefore re-
sults in fewer side effects and less risk of dyspigmentation. It has
also been suggested that the microscopic injury zones that are caused
by fractionated ablation allow for the transport of necrotic epidermal
debris including melanin through the DEJ. Early results with a
nonfractioned CO2 laser highlighted the risks for PIH.
Angsuwarangsee and Polnikorn (2003) performed a split-face
trial to study the efficacy of a Q-switched alexandrite 755-nm laser
with or without one pass of an ultrapulsed CO2 laser in six female
patients with refractory melasma. Three patients developed PIH on
both sides of the face 2 to 4 weeks postprocedure and one patient
developed hypopigmentation. Given the risk of postoperative
dyspigmentation, the authors concluded that neither modality was
safe enough to recommend for routine use to treat patients with
melasma (Angsuwarangsee and Polnikorn, 2003). Few trials with
fractional CO2 lasers have been completed to date. Trelles et al.
(2010) assigned 30 female patients with melasma to one of three
treatment groups: topical melasma cream (Kligman’s formula), CO2
ablative fractional resurfacing, and a combination of both treatments.
The results of the patients who underwent combined treatment with
CO2 laser and long-term topical lightening cream showed the
greatest improvement and were able to maintain the treatment ben-
efits up to the 12-month posttreatment. Patients in the other groups
were unable to sustain their initial improvement (Trelles et al., 2010).
The cutaneous absorption of the Er:YAG laser energy by water
(2940 nm) is 10-fold more efficient than that of the carbon dioxide
laser and allows for more superficial tissue ablation but with minimal
thermal damage. There are very few studies on the use of
erbium:YAG to treat patients with melasma. Manaloto and Alster
(1999) treated 10 female patients with refractory melasma using
erbium:YAG laser at energy levels of 5.1 J/cm to 7.6 J/cm. There was
a marked improvement of melasma immediately posttreatment.
However, between 3 and 6 weeks postoperatively, all patients devel-
oped PIH despite the use of oral steroid drugs for 5 days
postprocedure (Manaloto and Alster, 1999). Wanitphakdeedecha
et al. (2009) treated 20 female patients with epidermal melasma
monthly for a total of two treatments with an Er:YAG laser. Both mel-
anin index and MASI score showed a significant improvement at the
2-month but not the 4-month follow-up visit. Furthermore, clinical
improvement as assessed by dermatologists who were blinded to
the treatment showed that only 15% of patients sustained improve-
ment that was greater than 50% after 4 months of follow-up
(Wanitphakdeedecha et al., 2009).
Picosecond lasers
Recent innovations in laser design have introduced a new class of
lasers that generate picosecond-domain pulses. Shorter laser pulse
durations result in pigment fragmentation that is more a result of
16 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
photoacoustic than photothermal effects. Therefore, it may be more
efficient at pigment removal without inducing thermal damage to
surrounding tissue. This thermal damage seems to be the greatest
drawback of conventional Q-switched laser treatment for patients
with melasma and likely the cause of the high PIH rates after
treatment.
Picosecond lasers are currently available with laser outputs of 532
nm, 755 nm, and 1064 nm. Thus far, however, no data has been pub-
lished about their efficacy in patients with melasma either using set-
tings for benign pigmented lesions like solar lentigos or at low
fluence treatments that are analogous to low fluence Q-switched
laser treatment. More recently, fractionated picosecond handpieces
have been developed for the purpose of resurfacing and rejuvenation.
Only a few clinical studies have been completed with these new de-
vices and thus far, no results with regard to melasma have been re-
ported. Due to the potential of picosecond lasers to work via
photoacoustic mechanisms, they may present a new treatment mo-
dality that is suitable for patients with melasma.
Other laser treatments
Other types of laser therapy include pulsed dye lasers (PDL; 585
nm) and copper bromide (CuBr; 511-578 nm) lasers, which are
thought to work by targeting the vascular component of melasma.
Passeron and colleagues published a study in 2011 that combined
PDL therapy at purpuric settings with triple combination topical thera-
py. The combination therapy was beneficial in patients with Fitzpatrick
skin types II and III but half of the patients with darker skin developed
PIH (Passeron et al., 2011). An early 2010 study by Lee and colleagues
of four women who had telangiectatic erythema within their melasma
suggested that targeting the vascular component with a CuBr laser led
to reduced MASI scores (Lee et al., 2010). However, two follow-up
studies, one with CuBr laser only (Eimpunth et al., 2014) and the
other with combined CuBr laser/triple combination topical therapy
(Hammami Ghorbel et al., 2015) failed to demonstrate effectiveness.
Overall, targeting vascularity as a treatment for patients with melasma
has not shown a significant benefit.
Future roles of lasers or other devices in the treatment of melasma
In the future, lasers or other devices may contribute to the treat-
ment of patients with melasma not only by targeting pigment
Entry Pathways
Sunlight
Hormones
Inflammation
Melasma
Tretinoin
Chemical peels
Exit Pathways
Figure 1. Mechanistic Overview of Melasma Pathology and the Effects of Topical and Laser/Light/Device Procedures
directly but by facilitating the delivery of topical medications, which
is a technique that is known as laser-assisted drug delivery (LADD).
Currently, most topical therapeutic treatments have poor bioavail-
ability due to the difficulty to penetrate the skin barrier. With
LADD, CO2 or Erb:Yag ablative lasers create a matrix of trans-
epidermal channels that provide direct access to deeper layers of
the skin and facilitate cutaneous and transcutaneous drug delivery.
By manipulating the density and depth of these channels, it appears
possible to manipulate the amount of drug that is absorbed, the deliv-
ery rate, and the drug biodistribution, which may lead to improved
clinical efficacy. LADD with ablative lasers has the largest body of ev-
idence for efficacy and particularly as a pretreatment to enhance the
penetration of aminolevulonic acid or methylaminolevulinate prior
to photodynamic therapy (Haedersdal et al., 2016). However, studies
are ongoing to assess the delivery of numerous substances with mul-
tiple laser modalities (Haedersdal et al., 2016; Zaleski-Larsen and
Fabi, 2016). At least one recent study has shown the potential of
nonablative fractional lasers to deliver small- and macro-molecules
(Lee et al., 2016). The hope is that LADD may offer a more effective
way to deliver medications especially for the dermal type of melasma
for which topical delivery seems to be out of reach and has limited
success.
Analogous to LADD, microneedle (MN) technology creates
micron-sized pores through the epidermis to facilitate the transport
of therapeutic molecules into the epidermis. Instead of a laser,
microneedling uses a roller device with hundreds of micron-length
needles that create an array of pores to act as aqueous transport path-
ways through the stratum corneum. These micropores are larger than
the pores that are created by LADD and may permit the transport of
hydrophilic macromolecules, peptides, deoxyribonucleic acid, and
small interfering ribonucleic acid constructs (Donnelly et al., 2010).
MNs are now exploited in the cosmeceutical industry as a means to
disrupt the skin cell architecture and induce elastin and collagen ex-
pression and deposition. They are also used as a means to deliver
cosmeceutic molecules across the skin (McCrudden et al., 2015).
At least one small retrospective study has suggested that MN may
improve melasma. In this study, 22 patients with Fitzpatrick skin
types I to III, Wood’s lamp testing confirmed melasma that is recalci-
trant to sun protection and topical lightening creams completed two
MN treatments one month apart. The MN device had needles that
were 1.5 mm in length and the technique required back and forth
movements approximately ten times in four different directions.
melanin production
melanosome transfer
Tyrosinase
or PAR-2
inhibitors
NAFL
IPL
Q-switched Laser
Radiofrequency
 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
Table 1
Proposed therapeutic ladder for melasma
First-line Therapy Control of risk factors (sun protection, discontinue
hormone treatments or photosensitizing medications)
- Topical anti-Tyrosinase therapy
- Other inhibitors of the melanin synthetic pathway
(e.g., protease-activated receptor-2 inhibitor)
- Topical exfoliant
- Triple combination topical cream, if tolerated
Second-line Therapy Combination of first-line treatments +
series chemical peels
Third-line Therapy Combination of first-line treatments with:
- NAFL (1927 nm)
- NAFL (1550 nm, 1540 nm, or 1440 nm)
- Fractional radiofrequency devices
Fourth-line Therapy Combination of first line treatments with:
- Intense pulsed light (test spots)
- Q-switch laser
NAFL, nonablative fractional laser.
Within 24 hours of treatment, patients were instructed to apply a
combination of 0.05% tretinoin, 4% hydroquinone, and 1% fluo-
cinolone acetonide daily and maintain the topical regimen for at
B Pre Treatment
Figure 2. A. Non ablative fractionated laser treatment zones by depth of penetration B. Response to a single treatment of non ablative fractionated 1927 nm laser (Fraxel, Solta, 20mJ/mb,
TL 2, Passes 8).
17
least 30 days after treatment. Patients were judged subjectively by
the investigator who indicated that all 22 patients had some degree
of improvement (Lima, 2015).
Radiofrequency (RF) devices have become much more popular in
the last few years due to their efficacy in tightening and rejuvenation,
high safety profile, and minimal posttreatment recovery time. RF de-
vices create an electrical current that, when in contact with tissue, en-
counters impedance and creates heat energy that in turn stimulates
collagen production. Furthermore, RF technology is independent of
pigment; therefore, it is safe to use in patients of all skin types and
has a low risk of hyperpigmentation unless too much bulk heating
occurs or arc burns are created on the surface of the skin from in-
adequate contact with the skin.
One study used a monopolar RF device to facilitate the drug delivery
of phytocomplex of 1% kojic acid in 50 patients who were treated
weekly for 6 weeks and evaluated pretreatment, at 1 month, and at
6 months. There was sustained MASI score improvement after
1 month that seemed to continue without adverse effects until the
6-month follow-up visit (Cameli et al., 2014). Fractional RF is a new
development in which pins are inserted into the skin, which results
in fractional treatments that range from nonablative to minimally
ablative. The pins vary in depth and density and some are even
Post Treatment
18 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20

silicone-coated at the base to minimize epidermal damage. Concep- Table 3

tually, this is a promising device for patients with melasma given Proposed post-treatment regimen

its ability to create fractionated transepidermal elimination of mela- Immediate Posttreatment Topical Tyrosinase inhibitor immediately
nin with minimal risk of postinflammatory hyperpigmentation. Fur- posttherapy High potency topical corticosteroid
thermore, we can utilize the technology for LADD similar to MN two times daily for 3 days postprocedure
Two Weeks Posttreatment Control of risk factors (sun protection,
(Chandrashekar et al., 2014).
discontinue hormone treatments) with:

- Topical anti-Tyrosinase therapy daily

Discussion and conclusion - Other inhibitors of the melanin synthetic
pathway (e.g., PAR-2 inhibitor)
Long-term Posttreatment Control of risk factors (sun protection,
The mechanism of melasma remains to be fully elucidated but
discontinue hormone treatments) with:
current research suggests it is a multifactorial condition where path-
ways of pigment homeostasis are disrupted in the epidermis, extra- - Topical anti-Tyrosinase therapy daily
- Other inhibitors of the melanin synthetic
cellular matrix, and dermis (Kwon et al., 2016). The sum of these
pathway (e.g., PAR-2 inhibitor)
changes is that the pathways for pigment production are greater - Resume topical exfoliant daily, if tolerated
than the sum of the pathways for pigment elimination (Fig. 1). As a - Resume triple combination topical cream,
result, melanosomes accumulate at the DEJ, the papillary dermis, or if tolerated
deeper. PAR-2, protease-activated receptor-2.
Laser and light therapy for the treatment of melasma is best suited
for patients with refractory melasma who failed with topical treat-
ment or a series of chemical peels. Topical therapy takes at least
have been tested so far is the synergism between topical anti-
three months or longer to see skin lightening and those patients
Tyrosinase treatment and the laser and light procedure. In general,
who are interested in a more rapid response could consider laser
pretreatment and posttreatment topical regimens in conjunction
and light therapy. A proposed therapeutic ladder for melasma is indi-
with laser and light treatment helps reduce the risk for rebound hy-
cated in Table 1. Counseling prior to treatment should disclose that
perpigmentation, postinflammatory pigmentation, and increases
procedural treatments are not cures for melasma but studies have
the longevity of the lightening effect on melasma. To control risk fac-
shown that lightening of the affected skin can occur after a series of
tors for melasma by use of avid sun protection and avoidance of hor-
treatments. Patients should also be counseled on the likelihood of re-
monal triggers is also important to maintain the benefits from laser
currence, PIH, and rebound hyperpigmentation. A significant number
treatment. Understanding what prior procedural treatment failures
of patients (approximately 50%) will have recurrence to some degree
the patient has experienced will generally help narrow the field of
within three to six months of their laser- and light-based procedure
alternative options to discuss.
regardless of the type of device used. The longest delay in recurrence
Patients with lighter-colored skin types (Fitzpatrick type I-III)
seems to be with NAFL treatments, IPL has an intermediate recur-
will generally have less risk for PIH or postinflammatory hypopig-
rence rate, and Q-switched lasers have the fastest rate of recurrence.
mentation. They may be more tolerant of any of the laser and light
However, limitations in interpreting these disparate clinical studies
treatment options that are presented above. Patients with darker
include varied skin phototypes and patient populations, variable
skin types (Fitzpatrick type IV-V) will likely have a higher risk with
grading systems used to assess improvement or recurrence and
Q-switched lasers, and IPL and NAFL treatment options may have a
very few of these studies are randomized controlled studies.
higher benefit-to-risk ratio and be better at blending the melasma-
The goal of melasma therapy is to limit the entry pathways and in-
affected areas with normal skin. If Q-switched lasers and IPL treat-
crease the exit pathways so that there is net loss of pigment. Once the
ments are used in patients with darker skin types, pretreatment
desired amount of lightening is achieved, the next step is to find a
test spots at the periphery of the affected areas that are completed
maintenance regimen that keeps the entry and exit pathways in equi-
several weeks before any larger surface areas treatment may be war-
librium. This may involve control of risk factors, topical treatments,
ranted but there is some debate as to whether or not these test spots
sporadic procedural treatments, or a mixture of these techniques.
are truly a good indication of whether someone will have adverse
The proper choice of procedural treatment will have to integrate
reactions.
the patient’s melasma-specific medical history, Fitzpatrick skin
Most of the clinical studies for laser- and light-based treatments
type, melasma type (epidermal, mixed, or dermal), other forms
are not categorized by type of melasma (epidermal, mixed, or der-
of hyperpigmentation that may be present within the melasma
mal). For some procedures such as NAFL, knowing the type of
sites, and pre- and post-procedure topical therapy and mainte-
melasma may be beneficial because the different NAFL wavelengths
nance treatments.
penetrate to different depths within the skin that are more likely to
The patient’s medical history and current and prior procedural
be effective. For instance, NAFL at 1927 nm penetrates just under
treatments for melasma are important. If no preventative treatment
the stratum corneum to a depth of 200 microns, NAFL at 1440 nm
or topical lightening regimen is used, a treatment regimen should
works from the DEJ to a depth of 300 micron, NAFL 1540 nm from
be initiated at least two to six weeks prior to the procedure treat-
the DEJ to725 microns, and NAFL at 1550 nm from the DEJ to 1350
ment. One unifying concept in all the laser and light therapies that
microns (Fig. 2a). The depth for each device is adjustable by changing
the fluence. A Wood’s lamp examination is probably sufficient to
highlight patients with a significant epidermal melasma component
Table 2 or mainly dermal melasma but provides little information about the
Proposed pretreatment regimen
depth of pigment within the dermis or the ratio or epidermal or der-
Two to Six Weeks Control of risk factors (sunprotection, mal melasma in mixed situations.
Pretreatment discontinue hormone treatments) with: Epidermal melasma is likely more responsive to NAFL at 1927 nm
- Topical anti-Tyrosinase therapy daily (Fig. 2B) whereas dermal melasma is likely more sensitive to NAFL at
- Other inhibitors of the melanin synthetic 1440-nm, 1540-nm, and 1550-nm wavelengths. As noninvasive
pathway (e.g., protease-activated receptor-2 imaging techniques such as reflectance confocal microscopy, electri-
inhibitor)
cal impedance spectroscopy, or optical coherence tomography
 M.K. Trivedi et al. / International Journal of Women's Dermatology 3 (2017) 11–20
improve, a better idea of the depth of treatment needed to treat pa-
tients with dermal melasma may become clearer. At this time, most
NAFL at 1440 nm, 1540 nm, and 1550 nm is done with settings that
are focused on the papillary or mid-dermis. Some of the suggested
mechanisms for melasma involve dermal extracellular abnormalities.
NAFL affects all the substrates within their microthermal treatment
zones, unlike Q-switched lasers or IPL that only target pigment itself.
Correction of these dermal abnormalities may be one reason why the
recurrence rate seems less with NAFL compared with Q-switched
lasers.
Studies of laser- and light-based treatments for patients with
melasma have shown that a long-term posttreatment maintenance
regimen is necessary to slow the recurrence of melasma and mini-
mize rebound hyperpigmentation or PIH. Also, limited studies have
suggested that skin immediately post-NAFL or AFL may be in a state
that facilitates the delivery of topical medications. To incorporate
these findings plus limit any inflammatory cascade from the laser
treatment or thermal injury, the following pre- and posttreatment
regimens are recommended prior to laser- and light-based treat-
ments (Tables 2 and 3).
Topical Tyrosinase inhibitors should be applied immediately after
the treatment is completed in addition to a high potency topical cor-
ticosteroid drug. The topical Tyrosinase inhibitor should be main-
tained at least daily for 2 weeks and the topical corticosteroid drug
should be maintained twice per day for an additional 3 days. After 2
weeks, a topical exfoliant such as tretinoin or a topical triple combi-
nation cream (anti-Tyrosinase, tretinoin, low potency steroid drug)
should be used daily. To optimize the benefit of topical therapy,
other agents that affect the melanin synthetic pathway such as Par-
2 inhibitors should be added to the pre- and posttreatment mainte-
nance regimen. Topical lightening agents may be irritating and the
risk of this postprocedure treatment is the balance of irritation from
the lightening agents that may result in PIH and the ability to deliver
the medication to the depth required for lightening, topical steroids
might help balance the irritant effect.
Light and laser therapy is an alternative approach to treat pa-
tients with recalcitrant melasma. The current methods are limited
by recurrence, postinflammatory dyspigmentation, and the need
for multiple treatments. However, as the treatments transitioned
from Q-switched lasers and IPL to NAFL, the recurrence rate and
number of treatments necessary to see benefits have decreased.
The treatment will continue to evolve as advances in laser or de-
vice technologies emerge. Imaging and drug delivery methods
can enhance these technologies, and it will be interesting to see
how the picosecond lasers and fractional radiofrequency devices
will impact melasma treatments.
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